Graft versus host disease (GVHD) and disease relapse remain obstacles to the efficacy of allogeneic stem cell transplantation (SCT). Adoptive immunotherapy with allogeneic activated natural killer (NK) cells in SCT is shown in murine models and early human studies to augment anti-tumor effects while preventing the incidence and severity of GVHD. However, utilizing donor-derived activated NK cells for cellular therapy is made difficult by suboptimal purification and ex-vivo expansion techniques. It is therefore proposed to utilize as the allogeneic NK source, the well characterized NK cell line, NK-92, which has the advantages of being a predictable, pure NK cell source, easily expandable, and already entered in phase I, FDA and IRB approved clinical trials in the U.S. A series of clinical studies, from phase I to III of NK-92 adoptive immunotherapy in allogeneic SCT, is planned. The phase I study will determine the safety and feasibility of adoptive immunotherapy with ex-vivo expanded NK-92 cells in allogeneic submyeloablative SCT to a maximum tolerated cell dose (MTD). A phase II study will take this MTD and examine the effect of NK-92 infusion on the endpoints of GVHD incidence and disease relapse. If the phase II study shows efficacy, a phase III study will proceed as a randomized, controlled trial comparing the efficacy of matched allogeneic SCT without NK-92 cell infusion as the control vs. matched allogeneic SCT with NK-92 cell infusion. Endpoints will be GVHD incidence, disease relapse, survival and comparison of GVHD prophylaxis - standard CSA/MTX vs. CSA/NK-92. These studies will also help to elucidate further the regulatory interactions between dendritic cells and NK cells that appear important in the pathogenesis of GVHD and present a potential target for preventive GVHD therapy, while maintaining anti-tumor effect. Well designed study of this novel adoptive cellular approach with NK-92 has the potential to substantially improve the outcome of allogeneic SCT and is the goal of a 5-year career development program in clinical research. [unreadable] [unreadable]